The Influence of BCL6 on the WNT Pathway in Glioblastoma Therapy Resistance

Glioblastoma is a devastating disease with a median survival of 18 months from diagnosis and a 5 years survival rate of only 10%. The gold standard of treatment for glioblastoma is surgical resection followed by chemotherapeutic treatment with Temozolomide, a DNA alkylating agent, and irradiation around the remaining tumour margins. These treatments are both designed to create DNA damage to the cancerous cells, causing the cell cycle to halt, and result in apoptosis. This treatment does extend patients life for a few months, however glioblastoma cells quickly become resistant to therapy, and disease is always fatal. The anti-apoptotic protein BCL6, confers resistance to apoptosis in response to DNA damage and has been shown to be upregulated in Glioblastoma in response to DNA damaging chemotherapy and irradiation. This upregulation has been hypothesised to increase resistance to these therapies. By minimizing resistance to the standard therapies, the outlook for sufferers of glioblastoma could be greatly improved. Dysregulation of the WNT pathway has also been shown to be very important in carcinogenesis of glioblastoma and is responsible for the diffuse nature of the tumour which makes total resection nearly impossible. An RNA-seq screen was carried out on a glioblastoma cell line in which BCL6 was inhibited using the small molecule inhibitor FX1. This resulted in a change in expression of a large number of WNT related genes. This indicates that there is a link between BCL6 and the WNT pathway. Changes in expression in the WNT genes DKK1, WNT5a and WNT5b were validated. Experiments were carried out to investigate the effects of chemotherapy and BCL6 inhibition on both the canonical and non-canonical WNT pathways. It was found that BCL6 has an influence of the level of activity of the canonical WNT pathway. It also influences migration, the cell cycle, and clonogenicity. Understanding this link between WNT and BCL6 could be crucial in finding an effective treatment for glioblastoma.